Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria
Abstract
:1. Introduction
2. Experimental Design
2.1. Virtual Screening
2.2. Chemistry
2.2.1. Synthesis of L-Tryptophan Methyl Ester (2)
2.2.2. General Procedure for the Synthesis of 3, 4, 5, 6, 8, and 9
2.2.3. Methyl (1S,3S)-1-(2-Methoxy)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (3)
2.2.4. Methyl (1R,3S)-1-(2-Methoxy)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (4)
2.2.5. Methyl (1S,3S)-1-(2-Chloro)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (5)
2.2.6. Methyl (1R,3S)-1-(2-Chloro)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (6)
2.2.7. 5-(Diethylamino)-2-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenol (8)
2.2.8. 1-(3,4,5-Trimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (9)
2.2.9. 1-(3,4,5-Trimethoxyphenyl)-9H-pyrido[3,4-b]indole (10)
2.3. Antimalarial Activity
2.3.1. Antiplasmodial Activity
2.3.2. In Vitro Cytotoxicity on Mammalian Cells
2.3.3. Selectivity Index (SI)
2.4. Evaluation of Physicochemical and Pharmacokinetic Properties
2.5. Evaluation of In Vivo Antimalarial Activity
2.5.1. Animals
2.5.2. Mouse Model of ECM
2.5.3. Drug Administration
2.5.4. Basic Indicator Evaluation
2.5.5. Macroscopic and Histological Analysis of the Brain
2.6. Evaluation of the In Silico and In Vitro Inhibition Potential of Nitric Oxide Synthesis
2.6.1. In Vitro Cytotoxicity against Mammalian Cells
2.6.2. Evaluation of Anti-Inflammatory Activity of Compound 10 by NO Dosage
2.6.3. Evaluation of the Interaction with iNOS by Molecular Docking Simulations
2.6.4. Statistical Analysis
3. Results and Discussion
3.1. Virtual Screening Results
3.2. Synthesis
3.3. Biological Evaluation
3.3.1. Cytotoxicity on Mammalian Cells and Antiplasmodial Activity
3.3.2. Evaluation of In Silico Physicochemical and Pharmacokinetic Parameters
3.3.3. In Vivo Antimalarial Activity
3.3.4. Evaluation of NO Production
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Compounds | ||||||||
---|---|---|---|---|---|---|---|---|
Models | Crystallographic Ligand | 3 | 4 | 5 | 6 | 8 | 9 | 10 |
2OK8 | −2.0 | −5.3 | −5.0 | −5.2 | −5.0 | −4.9 | −4.8 | −4.7 |
2PML | −6.9 | −9.0 | −8.8 | −9.4 | −9.0 | −8.6 | −7.9 | −8.8 |
4N0Z | −4.3 | −5.8 | −6.1 | −6.1 | −6.3 | −5.6 | −5.3 | −5.5 |
PfATP6 | −7.2 | −8.9 | −8.3 | −9.0 | −8.8 | −7.8 | −7.4 | −7.4 |
Compounds | P. falciparum IC50 ± SD (μM) * | WI-26-VA4 IC50 ± SD (μM) * | SI |
---|---|---|---|
3 | 0.71 ± 0.012 | >100 | >141 |
4 | 1.04 ± 0.021 | >100 | >96 |
5 | 1.41 ± 0.018 | >100 | >71 |
6 | 0.67 ± 0.019 | >100 | >149 |
8 | 1.82 ± 0.011 | >100 | >55 |
9 | 1.12 ± 0.014 | >100 | >89 |
10 | 0.51 ± 0.011 | >100 | >196 |
ART ** | 0.095 ±0.010 | >100 | >1000 |
CQ *** | 0.59 ± 0.015 | >100 | >169 |
Compound | HIE (p) | Caco-2 (p) | BBB (p) |
---|---|---|---|
3 | +(0.98) | +(0.84) | +(0.95) |
4 | +(0.98) | +(0.84) | +(0.95) |
5 | +(0.98) | +(0.87) | +(0.97) |
6 | +(0.98) | +(0.87) | +(0.97) |
10 | +(0.99) | +(0.82) | +(0.96) |
CQ | +(0.99) | +(0.66) | +(1.00) |
Compound | Dosage (mg/Kg) | Parasitemia ± SD (% Reduction) | n | |
---|---|---|---|---|
5th dpi | 7th dpi | |||
3 | 10 | 1.87 ± 1.02 b (41.19) | 7.50 ± 2.49 (0) | 10 |
4 | 10 | 0.79 ± 0.63 a,b (75.16) | 5.48± 3.64 (20.00) | 10 |
5 | 10 | 5.00 ± 1.59 (0.00) | 7.20 ± 4.57 (0) | 10 |
6 | 10 | 1.13 ± 0.48 a,b (64.36) | 5.48 ± 3.27 (0) | 10 |
10 | 10 | 1.02 ± 0.93 a,b (67.92) | 8.37 ± 2.26 (0) | 10 |
CQ * | 10 | 0.24 ± 0.05 a (96.5) | 0.21 ± 0.27 a (96.1) | 09 |
Water | - | 3.18 ± 2.68 | 6.85 ± 2.57 | 13 |
Compound | Dosage (mg/Kg) | Parasitemia ± SD (% Reduction) | n | |
---|---|---|---|---|
5th dpi | 7th dpi | |||
3 | 10 | 3.56 ± 2.57 (0.00) | 7.96 ± 3.26 (0) | 10 |
4 | 10 | 1.88 ± 2.46 b (40.88) | 6.18 ± 4.75 (9.78) | 10 |
10 | 10 | 0.57 ± 0.94 a,b (82.07) | 3.72 ± 3.93 b (45.69) | 10 |
CQ * | 10 | 0.24 ± 0.05 a (96.5) | 0.21 ± 0.27 a (96.1) | 9 |
Water | - | 3.18 ± 2.68 | 6.85 ± 2.57 | 13 |
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Alves, F.d.M.; Bellei, J.C.B.; Barbosa, C.d.S.; Duarte, C.L.; Fonseca, A.L.d.; Pinto, A.C.d.S.; Raimundo, F.O.; Carpinter, B.A.; Lemos, A.S.d.O.; Coimbra, E.S.; et al. Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria. Pathogens 2022, 11, 1529. https://doi.org/10.3390/pathogens11121529
Alves FdM, Bellei JCB, Barbosa CdS, Duarte CL, Fonseca ALd, Pinto ACdS, Raimundo FO, Carpinter BA, Lemos ASdO, Coimbra ES, et al. Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria. Pathogens. 2022; 11(12):1529. https://doi.org/10.3390/pathogens11121529
Chicago/Turabian StyleAlves, Fernanda de Moura, Jessica Correa Bezerra Bellei, Camila de Souza Barbosa, Caíque Lopes Duarte, Amanda Luisa da Fonseca, Ana Claudia de Souza Pinto, Felipe Oliveira Raimundo, Bárbara Albuquerque Carpinter, Ari Sérgio de Oliveira Lemos, Elaine Soares Coimbra, and et al. 2022. "Rational-Based Discovery of Novel β-Carboline Derivatives as Potential Antimalarials: From In Silico Identification of Novel Targets to Inhibition of Experimental Cerebral Malaria" Pathogens 11, no. 12: 1529. https://doi.org/10.3390/pathogens11121529